P2 Receptors as Therapeutic Targets in the Salivary Gland: From Physiology to Dysfunction

Abstract

Although often overlooked in our daily lives, saliva performs a host of necessary physiological functions, including lubricating and protecting the oral cavity, facilitating taste sensation and digestion and maintaining tooth enamel. Therefore, salivary gland dysfunction and hyposalivation, often resulting from pathogenesis of the autoimmune disease Sjögren's syndrome or from radiotherapy of the head and neck region during cancer treatment, severely reduce the quality of life of afflicted patients and can lead to dental caries, periodontitis, digestive disorders, loss of taste and difficulty speaking. Since their initial discovery in the 1970s, P2 purinergic receptors for extracellular nucleotides, including ATP-gated ion channel P2X and G protein-coupled P2Y receptors, have been shown to mediate physiological processes in numerous tissues, including the salivary glands where P2 receptors represent a link between canonical and non-canonical saliva secretion. Additionally, extracellular nucleotides released during periods of cellular stress and inflammation act as a tissue alarmin to coordinate immunological and tissue repair responses through P2 receptor activation. Accordingly, P2 receptors have gained widespread clinical interest with agonists and antagonists either currently undergoing clinical trials or already approved for human use. Here, we review the contributions of P2 receptors to salivary gland function and describe their role in salivary gland dysfunction. We further consider their potential as therapeutic targets to promote physiological saliva flow, prevent salivary gland inflammation and enhance tissue regeneration.

Radiation-Induced Salivary Gland Dysfunction: Mechanisms, Therapeutics and Future Directions

“…In response to γ-irradiation, both human and murine cell lines have been shown to release ATP, thereby activating G protein-coupled P2Y [ 110 , 129 , 135 ] and ATP-gated ionotropic P2X receptors [ 126 , 136 ], which initiate purinergic signaling. Although no studies have yet investigated this bystander effect in IR-induced salivary gland dysfunction, we and others have reported on the expression of P2Y 2 , P2X7 and P2X4 receptors in salivary gland epithelia of mice [ 137 , 138 , 139 ] and humans [ 139 ], suggesting that irradiated salivary glands in vivo should be highly sensitive to elevated levels of IR-induced eATP release. Mechanisms of P2 receptor signaling relevant to the bystander effect have been investigated in multiple tissues [ 110 , 122 , 123 , 124 , 125 , 126 , 127 , 128 ] and their potential roles in IR-induced salivary gland damage are summarized in Figure 3 .…”

Purinergic Signaling in Pancreas—From Physiology to Therapeutic Strategies in Pancreatic Cancer

“…In immune cells, activation of P2XR causes loss of intracellular K + and activation of pro-inflammatory pathways [87]. P2XR are widely expressed in epithelia (respiratory, urogenital, kidney, gastrointestinal) and especially in exocrine glands, such as salivary, tear glands and pancreas, where they, by means of Ca 2+ transients/influx, regulate secretion [64,88].…”

“…Specific agonists/inhibitors show that stimulation of these two receptors increases the proliferation of PANC-1 cells [142]. In addition, P2Y 1 R may contribute to tissue development in glands, e.g., salivary glands [88], and in pancreas, recent studies show that P2Y 1 R is an additional marker on pancreatic and duodenal homeobox 1 (PDX1) progenitor-like cells from human pancreatic tissue [143].…”

Saliva Metabolomics in Dry Mouth Patients with Head and Neck Cancer or Sjögren’s Syndrome

“…Dry mouth may lead to deteriorated oral health, including caries, Candida infection, distorted taste, and pronounced difficulties with speech and swallowing, severely reducing the person's quality of life. Dry mouth affects >95% of head and neck cancer (HNC) patients treated with radiotherapy and patients with the autoimmune disease primary Sjögren's syndrome (pSS) [1,2]. However, tissue damage after irradiation in HNC and autoimmuneinduced salivary gland destruction in pSS represent different etiologies of dry mouth affliction [3].…”

“…Thus, muscarinic agonists have been used as saliva stimulants when Cells 2022, 11, 323 2 of 14 some functional salivary gland tissue is present [5]. Additionally, purinergic receptors have recently been suggested as therapeutic targets to increase salivary secretion [1].…”